Bacteriostatic versus bactericidal antibiotics for patients with ... · between bactericidal and bacteriostatic antibiotics. This approach introduces a meta-level that is beyond the

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Year: 2015

Bacteriostatic versus bactericidal antibiotics for patients with seriousbacterial infections: systematic review and meta-analysis

Nemeth, Johannes ; Oesch, Gabriela ; Kuster, Stefan P

Abstract: OBJECTIVES Antibiotics are commonly classified into bactericidal and bacteriostatic agentsbased on their antimicrobial action. We aimed to assess whether this distinction is clinically relevant.METHODS OVID MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials (CEN-TRAL) and relevant references and conference proceedings using the Web of Science and Scopus databaseswere searched for randomized controlled trials comparing bactericidal with bacteriostatic antibiotics fortreatment of severe infections. Main outcome measures were clinical cure rates and overall mortality.Abstracts of studies selected in the database search were screened by one reviewer; full-text screeningand data extraction were performed by three independent reviewers. RESULTS Thirty-three studieswere included. Approximately half of patients were treated with bacteriostatic monotherapy. Infectionscovered were pneumonia (n = 13), skin and soft tissue infections (n = 8), intra-abdominal infections(n = 4) and others (n = 8). Neither clinical cure rates [risk ratio (RR), 0.99; 95% CI, 0.97-1.01; P =0.11] nor mortality rates (RR, 0.91; 95% CI, 0.76-1.08; P = 0.28) were different between patients treatedwith bactericidal drugs and those treated with bacteriostatic drugs. Subgroup analyses showed a benefitfor clinical cure rates associated with linezolid and increased mortality associated with tigecycline. Inmeta-regression, clinical cure rates remained higher in patients treated with linezolid (P = 0.01); tige-cycline displayed a close to significant association with increased mortality (P = 0.05) if compared withother bacteriostatic agents. CONCLUSIONS The categorization of antibiotics into bacteriostatic andbactericidal is unlikely to be relevant in clinical practice if used for abdominal infections, skin and softtissue infections and pneumonia. Because we were not able to include studies on meningitis, endocarditisor neutropenia, no conclusion regarding these diseases can be drawn.

DOI: https://doi.org/10.1093/jac/dku379

Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-105799Journal ArticlePublished Version

Originally published at:Nemeth, Johannes; Oesch, Gabriela; Kuster, Stefan P (2015). Bacteriostatic versus bactericidal an-tibiotics for patients with serious bacterial infections: systematic review and meta-analysis. Journal ofAntimicrobial Chemotherapy, 70(2):382-395.DOI: https://doi.org/10.1093/jac/dku379

https://doi.org/10.1093/jac/dku379

https://doi.org/10.5167/uzh-105799

https://doi.org/10.1093/jac/dku379

Bacteriostatic versus bactericidal antibiotics for patients with seriousbacterial infections: systematic review and meta-analysis

Johannes Nemeth1*†, Gabriela Oesch2† and Stefan P. Kuster1†

1Division of Infectious Diseases and Hospital Epidemiology, University Hospital and University of Zurich, Zurich, Switzerland;2University Children’s Hospital, Zurich, Switzerland

*Corresponding author. Tel: +41-44-255-21-73; Fax: +41-44-255-44-33; E-mail: [email protected]†The authors contributed equally to this work.

Received 2 July 2014; returned 11 August 2014; revised 26 August 2014; accepted 27 August 2014

Objectives: Antibiotics are commonly classified into bactericidal and bacteriostatic agents based on theirantimicrobial action. We aimed to assess whether this distinction is clinically relevant.

Methods: OVID MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL) and relevantreferences and conference proceedings using the Web of Science and Scopus databases were searched forrandomized controlled trials comparing bactericidal with bacteriostatic antibiotics for treatment of severe infec-tions. Main outcome measures were clinical cure rates and overall mortality. Abstracts of studies selected in thedatabase search were screened by one reviewer; full-text screening and data extraction were performed by threeindependent reviewers.

Results: Thirty-three studies were included. Approximately half of patients were treated with bacteriostaticmonotherapy. Infections covered were pneumonia (n¼13), skin and soft tissue infections (n¼8), intra-abdominal infections (n¼4) and others (n¼8). Neither clinical cure rates [risk ratio (RR), 0.99; 95% CI, 0.97–1.01; P¼0.11] nor mortality rates (RR, 0.91; 95% CI, 0.76–1.08; P¼0.28) were different between patients treatedwith bactericidal drugs and those treated with bacteriostatic drugs. Subgroup analyses showed a benefit for clin-ical cure rates associated with linezolid and increased mortality associated with tigecycline. In meta-regression,clinical cure rates remained higher in patients treated with linezolid (P¼0.01); tigecycline displayed a close tosignificant association with increased mortality (P¼0.05) if compared with other bacteriostatic agents.

Conclusions: The categorization of antibiotics into bacteriostatic and bactericidal is unlikely to be relevant inclinical practice if used for abdominal infections, skin and soft tissue infections and pneumonia. Becausewe were not able to include studies on meningitis, endocarditis or neutropenia, no conclusion regarding thesediseases can be drawn.

Keywords: drug classes, mechanism of action, generalizability

IntroductionThe distinction between bactericidal and bacteriostatic antibioticsis a successful concept to discriminate antibiotics that killbacteria—‘bactericidal’—from antibiotics that inhibit bacterialgrowth, i.e. ‘bacteriostatic’. This classification is applied in majortextbooks of medicine and infectious diseases, clinical guidelinesand advertisements of novel antibiotics.1 – 5 The intuitively under-standable concept between the two groups of antibiotics sug-gests that bactericidal drugs have more powerful antibacterialaction and are able to kill bacteria. In contrast, bacteriostatic anti-biotics are assumed to require phagocytic cells to definitely clearbacteria and are therefore thought to be less effective withoutan efficient immune response. This theoretical model has led to

the recommendation that severely ill and immunosuppressedpatients with bacterial infections should be treated with bacteri-cidal antibiotics.2 – 4 Furthermore, some specific conditions arealso thought to require bactericidal antibiotics, such as endocar-ditis.1 The cardiac valves are considered as focal, immunosup-pressed regions poorly accessible for phagocytic cells. Therefore,a phagocyte-independent killing by bactericidal drugs is generallyrecommended under such circumstances.

Unfortunately, there are no clinical data supporting the con-cept of bacteriostatic versus bactericidal antibiotics. This is quiteremarkable given the major influence on recommendations fortreatment of severely ill patients. The reason may lie in the diffi-culties of assessing a drug class effect in a clinically meaning-ful way.

# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.For Permissions, please e-mail: [email protected]

J Antimicrob Chemother 2015; 70: 382–395doi:10.1093/jac/dku379 Advance Access publication 28 September 2014

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The main challenge is that during bacterial infection andits treatment, relevant clinical outcomes such as cure rates andmortality are influenced by three main factors: the host, thepathogen and the drug. A drug class effect can only be secondaryto these three main factors and is therefore difficult to assess. Ourmethodological assumption was that the drug class effect ‘bac-tericidal versus bacteriostatic’ may be measurable if the threemain factors—host, drugs and pathogens—are as heterogeneousas possible. If the common denominator is limited to the differ-ence between bacteriostatic and bactericidal drugs amongst dif-ferent clinical trials, the results may be reduced to the differencebetween bactericidal and bacteriostatic antibiotics. This approachintroduces a meta-level that is beyond the range of a single ran-domized trial. We therefore conducted a meta-analysis includinga wide variety of prospective clinical trials using bacteriostatic ver-sus bactericidal antibiotic drugs for the treatment of patients withsevere bacterial infections. The main outcome measures wereclinical outcome and overall mortality.

Methods

Definitions

Severity

Requirement of hospitalization was used as a determinant to screen forseverity, unless the authors explicitly provided a definition for severityin the study. Studies including patients with different levels of severity,such as e.g. pneumonia and bronchitis, were excluded. Furthermore,studies performed with relatively benign infections were excluded(i.e. infections in the oral cavity, uncomplicated otolaryngeal infections,uncomplicated gastrointestinal infections, sexually transmitted diseases,Lyme disease, exacerbation of chronic bronchitis, pneumonia in the out-patient setting etc.). Chronic infections such as diabetic foot infectionswere excluded under the assumption that successful antibiotic therapyin this setting does not rely on rapid killing but rather elimination of the bio-film, vascular supply and joint and bone involvement.

Antibiotics

In the bacteriostatic antibiotic patient group, bacteriostatic single therapyonly without the concomitant use of any bactericidal drug was allowed,with few exceptions: if all three authors agreed that the bactericidal com-ponent of the combination therapy had no effect on bacteria, thesestudies were included as well. Seven studies met these criteria.6 – 12

Six out of seven allowed the use of aztreonam in case of infection withGram-positive bacteria; one study allowed aminoglycosides in case of pro-ven aminoglycoside resistance of Staphylococcus aureus infection.6 Therate of resistance was similar between bacteriostatic and bactericidal anti-biotics. For the seven studies with combination therapy, only the microbio-logically confirmed cases were extracted for analysis in the clinical curegroups. In all other studies, the ITT population was assessed. If no ITTpopulation was available, results from PP analyses were extracted.

In the bactericidal antibiotic treatment group, combination therapywas allowed. Antibiotics were defined as bactericidal and bacteriostaticaccording to a classification obtained from a major textbook of infectiousdiseases, with one important exception (Table 1).3 Aminoglycosides act atthe ribosome and are therefore classified as bacteriostatic by someauthors. At higher concentrations, however, aminoglycosides display avery rapid bactericidal effect. Due to considerations regarding side effects,aminoglycosides are recommended to be given once daily at high con-centrations for most indications.13 Therefore, aminoglycosides are mostlikely to be bactericidal in routine clinical practice and were classifiedaccordingly.

Studies using inappropriate antibiotics in terms of microbiologicalspectrum were excluded. Hence, possible differences are not attributableto resistance of bacteria.

Outcomes

For the primary endpoint, clinical outcome as defined by the respectivestudy authors was used. Secondary endpoints were mortality and relapserates. Relapse rates were defined as recurrence of signs and symptomsassociated with the primary infection during follow-up after initial clinicalresolution or ‘relapse’ as defined by the authors. Subgroup analyses for dif-ferent diseases were performed.

Data sources and searchesWith the help of an experienced librarian with expertise in literature searchfor systematic reviews and meta-analyses, we performed an electronicsearch of OVID MEDLINE, EMBASE and The Cochrane Central Register ofControlled Trials (CENTRAL). We also searched relevant references ofincluded studies and conference proceedings using the Web of Scienceand Scopus databases. No time limits were applied. The search strategyis displayed in detail in Figure S1 (available as Supplementary data atJAC Online).

Study selectionWe included all randomized controlled trials comparing bacteriostatic ver-sus bactericidal antibiotics in patients with serious bacterial infectionsrequiring hospitalization. There was no restriction by study site/countryor follow-up period and there was no restriction by dose, frequency ormethod of drug administration. One author (J. N.) screened the title andabstract of each reference identified by the search and applied the inclu-sion criteria. For possibly relevant articles, the full-text article was obtainedand reviewed independently by two out of the three authors (J. N.,G. O. and S. P. K.). Final inclusion of studies was determined by agreementof both reviewers and involvement of a third author in case of discrepancy.After in-depth discussion of the different opinions, the authors agreedunanimously on the final classification. Only studies published in Englishwere considered eligible.

Data extraction and quality assessmentTwo out of the three authors (J. N., G. O. and S. P. K.) independentlyextracted data from included trials. Data extraction was performed

Table 1. Definition of bacteriostatic and bactericidal antibiotics (adaptedfrom Cohen et al.3)

Bactericidalaminoglycosidesb-lactamsfluoroquinolonesglycopeptideslipopeptidesnitroimidazoles and nitrofurans

Bacteriostaticglycylcyclineslincosamidesmacrolidesoxazolidinonesstreptograminssulphonamides

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using a standardized data collection form. When missing data wereencountered, the corresponding authors were contacted to retrieve them.

For the assessment of clinical cure, data from ITT populations wereextracted if possible. Some studies did not report the clinical cure ratesof the ITTpopulation or—in case of older studies—did not discern betweendifferent study populations at all. In such a case, results from modifiedITT or PP populations were extracted. In case of the seven studies withcombination therapy, only the microbiologically confirmed cases wereextracted.6 – 12

For mortality analysis, the ITT (‘safety’) population was used through-out. The primary outcome measures were (i) clinical cure rate as definedby the investigators in the study and (ii) mortality rate. Data were extractedas proportions if results were only reported as probability of events ormortality and if the number of events was not explicitly provided.Unfortunately, follow-up data and periods of follow-up after end of treat-ment were heterogeneous.

Subgroup analysis was performed for different diseases and differentclasses of antibiotics. Meta-analysis was performed only if at least threestudies included the same disease or antibiotic.

To assess methodological quality and risk of bias, included articles wereexamined for (i) randomization process, (ii) blinding, (iii) incomplete out-come data and (iv) reporting bias/sponsorship as described in theCochrane Handbook for Systematic Reviews of Interventions.14

Data synthesis and analysisData synthesis was performed using Review Manager (version 5.2, TheCochrane Collaboration, The Nordic Cochrane Centre, Copenhagen,Denmark). P values ,0.05 were considered statistically significant.Subgroup analyses for differences between different classes of antibioticsand differences between different diseases were performed. Because het-erogeneity was anticipated between studies, a random-effects model wasused for all analyses. Statistical heterogeneity was inspected graphically(forest plot) and the degree of heterogeneity quantified using the I2 stat-istic. Publication bias was investigated using a funnel plot in which thestandard error of the effect estimate of each study was plotted againstthe estimate. An asymmetric plot suggested possible publication bias.

We used STATA 13 (StataCorp 2013, College Station, TX, USA) formeta-regression assessing differences between bacteriostatic drugclasses.

Results

Study selection

The literature search yielded 16490 references. After screeningtitles and abstracts, 81 articles were selected for full-text screen-ing (Figure 1). Thirty-three studies met the inclusion criteria(Table 2). The bacteriostatic agents included tigecycline, linezolid,macrolides, sulphonamides, tetracyclines and streptogramins.The bactericidal agents included b-lactam antibiotics, glycopep-tide antibiotics, fluoroquinolones and aminoglycosides. Diseasesunder study included pneumonia (13 studies6,11,15 – 19,21 – 26),skin and soft tissue infections (8 studies7,8,27 – 32), intra-abdominalinfections (4 studies33 – 36) and others (8 studies10,20,37 – 42). Notrials in neutropenic patients or patients with endocarditis or men-ingitis met inclusion criteria. All studies except one study on chil-dren with typhoid included adults only.37

Clinical cure rates

Data from 9597 patients were available for meta-analysis of clin-ical cure rates. Of these patients, 4717 (49.2%) were treated with

a bacteriostatic agent. Meta-analysis indicated that clinicalcure rates were not different between bactericidal and bacterio-static drugs [risk ratio (RR), 0.99; 95% CI, 0.97–1.01; P¼0.11;Figure 2], with an overall heterogeneity of I2¼24%. Analysis ofsubgroups was performed on studies using tigecycline, linezolid,macrolides, b-lactam antibiotics, glycopeptides and fluoroquino-lones. For the other drug classes, an insufficient number of studieswere found, precluding statistical analysis. Subgroup analysesrevealed that treatment with linezolid appeared to be associatedwith better clinical cure rates compared with its bactericidalcomparator (RR, 0.93; 95% CI, 0.87–0.99; P¼0.04; Figure 2). Inmeta-regression, combined cure rates of trials using linezolidwere better than those from tigecycline trials (RR, 1.07; 95% CI,1.02–1.12; P¼0.01). There was no benefit detectable for clinicalcure rates among subgroups of bactericidal antibiotics (Figure 3).

Mortality

The population for the assessment of mortality consisted of13098 patients in total. There was no significant increase in over-all mortality in the patient group treated with bacteriostatic anti-biotics compared with patients treated with bactericidalantibiotics (RR, 0.91; 95% CI, 0.76 –1.08; P¼0.28; Figure 4).Heterogeneity was low (I2¼0%). An increased mortality wasfound in studies using tigecycline in the bacteriostatic regimengroup (RR, 0.66; 95% CI, 0.46– 0.94; P¼0.02; Figure 4). Inmeta-regression, there was a strong trend towards reduced mor-tality in studies using linezolid compared with tigecycline trials(RR, 0.64; 95% CI, 0.41–1.00; P¼0.05). There was no mortalitybenefit detectable for subgroups of bactericidal antibiotics(Figure 5).

Relapse

In 12 studies, relapse rates were reported.7,8,17,18,20,34,35,37,39 – 42

Five studies included relapse rates in the clinical cure rate end-point.17,18,35,39,42 In the remaining seven studies, differences inrelapse rates between bacteriostatic and bactericidal antibioticswere not significant (RR, 0.76; 95% CI, 0.43–1.35; P¼0.51; datanot shown).

Title and abstract

674 references

Full paper screen

81 referencesExcluded

- Bactericidal antibiotics allowed in

bacteriostatic group (n = 24)

- Outpatients included (n = 9)

- No randomized controlled trial (n = 6)

- Poor quality of reporting (n = 6)

- Double publication (n = 3)

Analysed

33 studies

16 490 references

Figure 1. Study selection.

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Table 2. Study characteristics

Author Year Type of study Disease Antibiotics, bactericidalAntibiotics,

bacteriostatic

Bergallo et al.15 2009 Phase 3, multicentre, double-blind study community-acquired pneumonia levofloxacin tigecyclineBernard et al.27 1992 prospective, randomized,

multicentre trialcomplicated skin and soft tissue

infectionspenicillin roxithromycin

Bohte et al.16 1995 open-label, randomized,multicentre study

community-acquired pneumonia penicillin azithromycin

Breedt et al.28 2005 randomized, double-blind, controlled,multicentre trial

complicated skin and soft tissueinfections

vancomycin tigecycline

Chen et al.33 2010 Phase 3, multicentre, open-label study complicated intra-abdominal infection imipenem/cilastatin tigecyclineChuang et al.29 2011 two Phase 3, multicentre, randomized,

double-blind studiescomplicated skin and soft tissue

infectionsvancomycin/aztreonam tigecycline

Dartois et al.17 2008 randomized, Phase 3, multicentre trial community-acquired pneumonia levofloxacin tigecyclineEllis-Grosse et al.30 2005 two Phase 3, randomized, double-blind,

multicentre studiescomplicated skin and soft tissue

infectionsvancomycin/aztreonam tigecycline

Frenck et al.37 2000 randomized, open-label, controlled,single-centre trial

typhoid fever ceftriaxone azithromycin

Genne et al.18 1997 open-label, prospective, randomized,single-centre study

community-acquired pneumonia amoxicillin clarithromycin

Itani et al.7 2010 prospective, randomized, open-label,controlled, multicentre, Phase 4 study


vancomycin linezolid

Jauregui et al.8 2005 randomized, double-blind, controlled,multicentre, Phase 3 trial


dalbavancin linezolid

Kohno et al.38 2007 randomized, open-label,comparator-controlled,multicentre study

nosocomial pneumonia, complicatedskin and soft tissue infections or sepsiscaused by MRSA


Kuzman et al.19 2005 randomized, open-label,multicentre study

community-acquired pneumonia cefuroxime azithromycin

Lin et al.10 2008 randomized, double-blind,comparator-controlled,multicentre study

pneumonia or complicated skin and softtissue infection due to suspected orknown Gram-positive pathogens


Markowitz et al.39 1992 randomized, double-blind, comparative,single-centre study

infection with S. aureus vancomycin trimethoprim/sulfamethoxazole

Mehtar et al.20 1982 open-label, randomized,single-centre study

severe respiratory tract infections cefuroxime trimethoprim/sulfamethoxazole

Mwengee et al.40 2006 randomized, controlled, comparative,open-label trial

plague gentamicin doxycycline

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Table 2. Continued

Author Year Type of study Disease Antibiotics, bactericidalAntibiotics,

bacteriostatic

Mokabberi et al.21 2010 prospective, randomized, double-blind,single-centre trial

community-acquired pneumonia levofloxacin doxycycline

Ode et al.41 1983 open-label, randomized, prospective,single-centre, Phase 3 trial

acute pyelonephritis ampicillin/mecillinam trimethoprim/sulfamethoxazole

Oliva et al.34 2005 prospective, randomized, double-blind,multicentre trial

complicated intra-abdominal infection imipenem tigecycline

Plouffe et al.22 2000 two multicentre, open-label Phase 3trials, one parallel-group, randomized,one non-comparative with sequentialinclusion

community-acquired pneumonia cefuroxime azithromycin

Qvist et al.35 2012 randomized, open-label, multicentre,Phase 3b/4 trial

complicated intra-abdominal infections ceftriaxone/metronidazole tigecycline

Raad et al.42 1999 evaluator-blind, prospective,randomized, Phase 2, multicentre trial

catheter-related infections vancomycin quinupristin/dalfopristin

Sacchidanand et al.31 2005 Phase 3, randomized, double-blind,multicentre study


vancomycin/aztreonam tigecycline

San Pedro et al.11 2002 multicentre, randomized, open-label trial pneumonia with Streptococcuspneumoniae

ceftriaxone/cefpodoxime linezolid

Shanson et al.23 1984 prospective, randomized,single-centre trial

community-acquired pneumonia ampicillin/flucloxacillin erythromycin

Sterner et al.24 1967 randomized, open-label,single-centre trial

community-acquired pneumonia cefaloridine erythromycin

Stevens et al.32 2000 randomized, double-blind,multicentre trial

complicated skin and soft tissue infection oxacillin/dicloxacillin linezolid

Tanaseanu et al.26 2009 prospective, double-blind, non-inferiority,multicentre, Phase 3 trial

community-acquired pneumonia levofloxacin tigecycline

Tanaseanu et al.25 2008 two Phase 3, multicentre, randomized,double-blind studies

community-acquired pneumonia levofloxacin tigecycline

Towfigh et al.36 2010 multicentre, open-label, randomized,Phase 3b/4 study

complicated intra-abdominal infection ceftriaxone/metronidazole tigecycline

Wunderink et al.6 2012 prospective, double-blind, controlled,multicentre trial

confirmed MRSA pneumonia vancomycin linezolid

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Figure 2. RRs for clinical cure rates stratified by use of different bacteriostatic antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

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Figure 3. RRs for clinical cure rates stratified by use of different bactericidal antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

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Figure 4. RRs for mortality rates stratified by use of different bacteriostatic antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

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Figure 5. RRs for mortality rates stratified by use of different bactericidal antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

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Different diseases

We performed subgroup analyses of the most frequent diseases:abdominal infections, skin and soft tissue infections and pneumo-nia. No differences in clinical outcome between diseases could befound (Figure 6). However, increased mortality was detected inskin and soft tissue infections treated with bacteriostatic agents(RR, 0.43; 95% CI, 0.23–0.84; P¼0.01; Figure 7). If studies usingtigecycline were excluded, the difference was no longer significant(RR, 0.57; 95% CI, 0.26–1.27; P¼0.17), suggesting that this effectwas again due to the increased overall mortality attributed totigecycline. Notably, all four studies with abdominal infectionshad tigecycline in the bacteriostatic regimen arm without differ-ence in mortality.

Study quality

The quality of included studies was variable (Figures S2 and S3).More than half of studies (17/33) were unblinded, resulting in sig-nificant risk of performance bias. More than 50% of studies weresponsored by the pharmaceutical company that manufacturedthe respective drug and were thus regarded to be at high risk ofreporting bias. Funnel plots did not suggest publication bias(Figures S4–S7).

DiscussionIn our meta-analysis comparing bactericidal with bacteriostaticantibiotics, no significant differences in clinical cure rates werefound in the diseases under study. Subgroup analysis even sug-gested that linezolid may have better clinical cure rates if comparedwith its bactericidal comparators. This subgroup included severely illpatients with confirmed MRSA infections, amongst others.6,38

Sufficient antibacterial action of antibiotics in such a patient groupis therefore crucial. As a note of caution, involvement of the sponsorin the trials using linezolid was substantial and meta-analysisshowed some heterogeneity. Furthermore, vancomycin, which isdifficult to dose appropriately, was the comparator drug in themajority of studies. Therefore, it is premature to conclude thatlinezolid is more efficient than bactericidal antibiotics. However,our findings suggest that linezolid monotherapy is on par with thestandard bactericidal therapy in this patient group.

Our meta-analysis did not detect differences in overall mortal-ity between the patient groups. However, there was an increasedmortality associated with the use of tigecycline, an observation inline with data published recently.43 Meta-regression showeda trend towards increased mortality of patients treated with tige-cycline compared with linezolid. The association betweenincreased mortality and tigecycline was predominantly foundamongst patients with severe skin infections. Remarkably, mortal-ity was not increased in 931 patients treated with tigecycline forcomplicated intra-abdominal infections. An increased mortality inspecific patient populations without differences in clinical curerates may have various reasons, such as toxicity of the drug, phar-macokinetic/pharmacodynamic issues or other reasons.43 Someauthors suggest that the drug may be inadequately dosed,at least for ventilator-associated pneumonia.44 This may wellexplain observed breakthrough bacteraemias as well.45 Inconclusion, increased mortality is probably a specific feature oftigecycline and not a class effect inherent to all bacteriostatic

drugs. A possible difference from a previously published meta-analysis on tigecycline is the strict exclusion of concomitantbactericidal medication.43

It is important to note that the analysis of clinical cure rates andmortality includes two different populations. Clinical cure ratesincluded all patients who were followed up adequately; overalland including all the older studies, they represent a sample thatis closer to PP. The mortality analysis consists of safety data,resembling to a great extent an ITT population. These two popula-tions cannot be distinguished by contemporary definitions,because we included a substantial number of older studies.

Furthermore, it is important to note that the subgroup analysesare supportive of the main research question, i.e. whether a classeffect between bacteriostatic and bactericidal drugs is detectable.They should not be regarded as ‘independent’ investigations andtheir results should not be overemphasized.

Renowned textbooks suggest that immunocompromisedpatients should be treated with bactericidal antibiotics.3,4 Ouranalyses include a wide variety of serious bacterial infections,including respiratory tract infections, complicated abdominalinfections and skin infections. It is widely accepted that a centralpathogenetic feature of most bacterial infections is either local(e.g. disruption of the membrane integrity, such as injury of theskin serving for severe skin infection, or obstruction, such asappendicitis caused by luminal obstruction) or systemic immuno-suppression (e.g. neutropenia).46 As it is generally assumed thatbacteriostatic antibiotics require a fully functioning immune sys-tem to kill bacteria, one would expect differences in clinical curerates in the patient group receiving bacteriostatic drugs. Ourmeta-analysis suggests that this is not the case. Therefore, itmay be hypothesized that either the local immunosuppressionin respiratory tract infections, complicated abdominal infectionsand skin infections is not clinically relevant enough to requirethe presence of a bactericidal drug or that the biology of bacterialkilling is much more complex than the simplistic concept of bac-teriostatic versus bactericidal drug activity suggests, even in localimmunosuppression. In any case, our data suggest class indiffer-ence for infection where the immune system is intact or at leastnot impaired in a major way. Based on the data analysed, no con-clusions regarding severely immunosuppressed patients, such aspatients with neutropenia, can be drawn.

Because of our strict inclusion criteria, we were unable toinclude studies assessing neutropenic patients or patients withendocarditis. These are the ‘classical’ indications for a bactericidaldrug regimen. Only one randomized controlled trial using a bac-teriostatic drug—linezolid—in patients with neutropenia wasfound.47 Unfortunately, a bactericidal add-on medication wasallowed, precluding inclusion in our meta-analysis.47 Thus, thefindings from our work can only be applied to the diseasesunder study in our meta-analysis and may not be extended toendocarditis and neutropenia.

A major theoretical complication of bacteriostatic agents isrelapse of infection after treatment because of the failure toclear the infection. In the current investigation, there was nodetectable difference in relapse rates between bactericidal andbacteriostatic antibiotics.

Our study has limitations. To our knowledge, this is the firststudy to undertake a meta-analysis on a class effect of drugs.Therefore, we have no means to measure if the studies includedare heterogeneous enough regarding the three main factors

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(host, pathogen and drug) to conclude that the only differencebetween the two patient groups really is the difference betweenbacteriostatic and bactericidal antibiotics. There are, however,

sound arguments in favour of such a conclusion. Regarding thepathogen, we included studies on a wide array of diseases, ran-ging from Yersinia pestis to methicillin-resistant staphylococci.6,40

Figure 6. RRs for clinical cure rates stratified by different diseases. Data markers indicate RRs and error bars indicate 95% CIs.

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Figure 7. RRs for mortality rates stratified by different diseases. Data markers indicate RRs and error bars indicate 95% CIs.

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Regarding the host, patients with severe local infections such assevere skin infections or severe abdominal infections were ana-lysed as well as patients with systemic infections such as salmon-ellosis or central line-associated infections. Regarding the drugs, atotal of 10 different antibiotic classes were assessed. These differ-ent drugs may vary significantly in tissue distribution and mayhave different effects according to their dosing schedules.Amongst the bacteriostatic drugs, the newer drugs tigecyclineand linezolid are over-represented. The numbers of patientsincluded in clinical trials increases over time, probably due to a ris-ing standard in research practice. This may explain the observedover-representation of newer bacteriostatic drugs.

The included studies have a significant risk for performanceand publication bias. In general, there may be a publication biasin favour of bacteriostatic drugs—i.e. linezolid and tigecycline.However, some studies may have a publication bias in favour ofthe bactericidal component as well, as in the case of dalbavancincompared with linezolid.8

The microbiological definition of bacteriostatic versus bacteri-cidal suggests a degree of clarity that is not supported by theevidence. Some drugs labelled as ‘bacteriostatic’ do have ‘bacteri-cidal’ effects under some in vitro conditions and vice versa.48 Forexample, the exchange of culture media—media used for grow-ing of eukaryotic cells instead of ‘classical’ Mueller –Hintonbroth—may significantly affect drug susceptibility in vitro.49

Thus, it is probably very difficult to predict the action of a givenantibiotic drug in terms of bacteriostatic or bactericidal in anactual patient with an ongoing bacterial infection. Furthermore,the action of a given drug may be dependent on the bacterialload and the interaction with the immune system at the site ofinfection. For example, the capacity of neutrophils to phagocytosebacteria is limited by the sheer quantity of bacteria.50

To our knowledge, this is the first study using clinical data toinvestigate the difference between bactericidal and bacteriostaticantibiotics. Summarized, the data at hand suggest that this clas-sification is clinically irrelevant if used for abdominal infections,skin and soft tissue infections and pneumonia. These findingscannot be applied directly to patients with meningitis, neutro-penia or endocarditis, because we were unable to include thesetypes of infection in our meta-analysis.

AcknowledgementsWe are thankful for fruitful discussions with Rainer Weber, Nicolas Muller,Jan S. Fehr, Dominique L. Braun, Huldrych F. Guenthard, Ulrich Matt,Elisabeth and Titus Nemeth.

FundingThis study was carried out as part of our routine work.

Transparency declarationsNone to declare.

Author contributionsStudy concept and design: J. N., G. O. and S. P. K. Acquisition of data: J. N.,G. O. and S. P. K. Statistical analysis: J. N. and S. P. K. Analysis and interpret-ation of data: J. N., G. O. and S. P. K. Drafting of the manuscript: J. N. and

S. P. K. Critical revision of the manuscript for important intellectual content:J. N., G. O. and S. P. K.

Supplementary dataFigures S1 to S7 are available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).

References1 Habib G, Hoen B, Tornos P et al. Guidelines on the prevention, diagnosis,and treatment of infective endocarditis (new version 2009): the Task Forceon the Prevention, Diagnosis, and Treatment of Infective Endocarditis ofthe European Society of Cardiology (ESC). Endorsed by the EuropeanSociety of Clinical Microbiology and Infectious Diseases (ESCMID) andthe International Society of Chemotherapy (ISC) for Infection andCancer. Eur Heart J 2009; 30: 2369–413.

2 American Thoracic Society. Guidelines for the management of adultswith hospital-acquired, ventilator-associated, and healthcare-associatedpneumonia. Am J Respir Crit Care Med 2005; 171: 388–416.

3 Cohen J, Powderly WG, Opal SM et al. Infectious Diseases, 2 vols.Mosby, 2003.

4 Fauci A, Dennis L, Longo D et al. Harrison’s Principles of Internal Medicine.McGraw-Hill Professional, 2008.

5 Cubist Pharmaceuticals Inc. Lexington, MA, USA. http://www.cubicin.com/about.html.

6 Wunderink RG, Niederman MS, Kollef MH et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized,controlled study. Clin Infect Dis 2012; 54: 621–9.

7 Itani KM, Dryden MS, Bhattacharyya H et al. Efficacy and safety oflinezolid versus vancomycin for the treatment of complicated skin andsoft-tissue infections proven to be caused by methicillin-resistantStaphylococcus aureus. Am J Surg 2010; 199: 804–16.

8 Jauregui LE, Babazadeh S, Seltzer E et al. Randomized, double-blindcomparison of once-weekly dalbavancin versus twice-daily linezolid ther-apy for the treatment of complicated skin and skin structure infections.Clin Infect Dis 2005; 41: 1407–15.

9 Kohno S, Yamaguchi K, Aikawa N et al. Linezolid versus vancomycin forthe treatment of infections caused by methicillin-resistant Staphylococcusaureus in Japan. J Antimicrob Chemother 2007; 60: 1361–9.

10 Lin DF, Zhang YY, Wu JF et al. Linezolid for the treatment of infectionscaused by Gram-positive pathogens in China. Int J Antimicrob Agents2008; 32: 241–9.

11 San Pedro GS, Cammarata SK, Oliphant TH et al. Linezolid versus ceftri-axone/cefpodoxime in patients hospitalized for the treatment ofStreptococcus pneumoniae pneumonia. Scand J Infect Dis 2002; 34:720–8.

12 Stevens DL, Smith LG, Bruss JB et al. Randomized comparison of line-zolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of compli-cated skin and soft tissue infections. Antimicrob Agents Chemother2000; 44: 3408–13.

13 Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing inimmunocompetent adults: a meta-analysis. Ann Intern Med 1996; 124:717–25.

14 Cochrane Collaboration. Cochrane Handbook for Systematic Reviews ofInterventions. http://handbook.cochrane.org/.

15 Bergallo C, Jasovich A, Teglia O et al. Safety and efficacy of intravenoustigecycline in treatment of community-acquired pneumonia: results froma double-blind randomized phase 3 comparison study with levofloxacin.Diagn Microbiol Infect Dis 2009; 63: 52–61.

Systematic review





http://www.cubicin.com/about.html




http://handbook.cochrane.org/



16 Bohte R, van’t Wout JW, Lobatto S et al. Efficacy and safety of azithro-mycin versus benzylpenicillin or erythromycin in community-acquiredpneumonia. Eur J Clin Microbiol Infect Dis 1995; 14: 182–7.

17 Dartois N, Castaing N, Gandjini H et al. Tigecycline versus levofloxacinfor the treatment of community-acquired pneumonia: European experi-ence. J Chemother 2008; 20 Suppl 1: 28–35.

18 Genne D, Siegrist HH, Humair L et al. Clarithromycin versus amoxicillin-clavulanic acid in the treatment of community-acquired pneumonia. Eur JClin Microbiol Infect Dis 1997; 16: 783–8.

19 Kuzman I, Dakovic-Rode O, Oremus M et al. Clinical efficacy and safetyof a short regimen of azithromycin sequential therapy vs standard cefur-oxime sequential therapy in the treatment of community-acquired pneu-monia: an international, randomized, open-label study. J Chemother2005; 17: 636–42.

20 Mehtar S, Parr JH, Morgan DJ. A comparison of cefuroxime andco-trimoxazole in severe respiratory tract infections. J AntimicrobChemother 1982; 9: 479–84.

21 Mokabberi R, Haftbaradaran A, Ravakhah K. Doxycycline vs. levofloxa-cin in the treatment of community-acquired pneumonia. J Clin Pharm Ther2010; 35: 195–200.

22 Plouffe J, Schwartz DB, Kolokathis A et al. Clinical efficacy of intraven-ous followed by oral azithromycin monotherapy in hospitalized patientswith community-acquired pneumonia. The Azithromycin IntravenousClinical Trials Group. Antimicrob Agents Chemother 2000; 44: 1796–802.

23 Shanson DC, McNabb WR, Williams TD et al. Erythromycin comparedwith a combination of ampicillin plus flucloxacillin for the treatment ofcommunity acquired pneumonia in adults. J Antimicrob Chemother1984; 14: 75–9.

24 Sterner G, Fransen H, Tunevall G et al. A comparative trial of cephalor-idine and erythromycin in hospitalized pneumonic patients. Postgrad Med J1967; 43 Suppl 43: 53–4.

25 Tanaseanu C, Bergallo C, Teglia O et al. Integrated results of 2 phase 3studies comparing tigecycline and levofloxacin in community-acquiredpneumonia. Diagn Microbiol Infect Dis 2008; 61: 329–38.

26 Tanaseanu C, Milutinovic S, Calistru PI et al. Efficacy and safety of tige-cycline versus levofloxacin for community-acquired pneumonia. BMC PulmMed 2009; 9: 44.

27 Bernard P, Plantin P, Roger H et al. Roxithromycin versus penicillin in thetreatment of erysipelas in adults: a comparative study. Br J Dermatol1992; 127: 155–9.

28 Breedt J, Teras J, Gardovskis J et al. Safety and efficacy of tigecycline intreatment of skin and skin structure infections: results of a double-blindphase 3 comparison study with vancomycin-aztreonam. AntimicrobAgents Chemother 2005; 49: 4658–66.

29 Chuang YC, Chang CM, Aradhya S et al. Efficacy and safety of tigecyc-line monotherapy compared with vancomycin-aztreonam in the treat-ment of complicated skin and skin structure infections in patients fromIndia and Taiwan. J Microbiol Immunol Infect 2011; 44: 116–24.

30 Ellis-Grosse EJ, Babinchak T, Dartois N et al. The efficacy and safety oftigecycline in the treatment of skin and skin-structure infections: results of2 double-blind phase 3 comparison studies with vancomycin-aztreonam.Clin Infect Dis 2005; 41 Suppl 5: S341–53.

31 Sacchidanand S, Penn RL, Embil JM et al. Efficacy and safety of tigecyc-line monotherapy compared with vancomycin plus aztreonam in patientswith complicated skin and skin structure infections: results from a phase 3,randomized, double-blind trial. Int J Infect Dis 2005; 9: 251–61.

32 Stevens DL, Smith LG, Bruss JB et al. Randomized comparison of line-zolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of compli-cated skin and soft tissue infections. Antimicrob Agents Chemother2000; 44: 3408–13.

33 Chen Z, Wu J, Zhang Y et al. Efficacy and safety of tigecycline mono-therapy vs. imipenem/cilastatin in Chinese patients with complicatedintra-abdominal infections: a randomized controlled trial. BMC Infect Dis2010; 10: 217.

34 Oliva ME, Rekha A, Yellin A et al. A multicenter trial of the efficacyand safety of tigecycline versus imipenem/cilastatin in patients with compli-cated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW;ClinicalTrials.gov Identifier: NCT00081744]. BMC Infect Dis 2005; 5: 88.

35 Qvist N, Warren B, Leister-Tebbe H et al. Efficacy of tigecycline versusceftriaxone plus metronidazole for the treatment of complicatedintra-abdominal infections: results from a randomized, controlled trial.Surg Infect 2012; 13: 102–9.

36 Towfigh S, Pasternak J, Poirier A et al. A multicentre, open-label, rando-mized comparative study of tigecycline versus ceftriaxone sodium plusmetronidazole for the treatment of hospitalized subjects with complicatedintra-abdominal infections. Clin Microbiol Infect 2010; 16: 1274–81.

37 Frenck RW Jr, Nakhla I, Sultan Y et al. Azithromycin versus ceftriaxonefor the treatment of uncomplicated typhoid fever in children. Clin Infect Dis2000; 31: 1134–8.

38 Kohno S, Yamaguchi K, Aikawa N et al. Linezolid versus vancomycin forthe treatment of infections caused by methicillin-resistant Staphylococcusaureus in Japan. J Antimicrob Chemother 2007; 60: 1361–9.

39 Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazolecompared with vancomycin for the treatment of Staphylococcus aureusinfection. Ann Intern Med 1992; 117: 390–8.

40 Mwengee W, Butler T, Mgema S et al. Treatment of plague with genta-micin or doxycycline in a randomized clinical trial in Tanzania. Clin InfectDis 2006; 42: 614–21.

41 Ode B, Cronberg S, Flamholc L et al. Intravenous mecillinam, trimethoprimand ampicillin in acute pyelonephritis. Drugs Exp Clin Res 1983; 9: 337–43.

42 Raad I, Bompart F, Hachem R. Prospective, randomized dose-rangingopen phase II pilot study of quinupristin/dalfopristin versus vancomycinin the treatment of catheter-related staphylococcal bacteremia. Eur JClin Microbiol Infect Dis 1999; 18: 199–202.

43 Tasina E, Haidich AB, Kokkali S et al. Efficacy and safety of tigecycline forthe treatment of infectious diseases: a meta-analysis. Lancet Infect Dis2011; 11: 834–44.

44 Ramirez J, Dartois N, Gandjini H et al. Randomized phase 2 trial toevaluate the clinical efficacy of two high-dosage tigecycline regimens ver-sus imipenem-cilastatin for treatment of hospital-acquired pneumonia.Antimicrob Agents Chemother 2013; 57: 1756–62.

45 Cho SY, Kang CI, Chung DR et al. Breakthrough bacteremia due toextended-spectrum-b-lactamase-producing Klebsiella pneumoniae dur-ing combination therapy with colistin and tigecycline. Antimicrob AgentsChemother 2012; 56: 4994–5.

46 Mandell G, Bennett J, Dolin R. Principles and Practice of InfectiousDiseases. Philadelphia: Churchill Livingstone, 2010.

47 Jaksic B, Martinelli G, Perez-Oteyza J et al. Efficacy and safety of linezolidcompared with vancomycin in a randomized, double-blind study of febrileneutropenic patients with cancer. Clin Infect Dis 2006; 42: 597–607.

48 Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bac-tericidal mechanisms of action in the treatment of Gram-positive bacterialinfections. Clin Infect Dis 2004; 38: 864–70.

49 Buyck JM, Plesiat P, Traore H et al. Increased susceptibility ofPseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell cul-ture media and biological fluids due to decreased expression of oprM andincreased outer-membrane permeability. Clin Infect Dis 2012; 55: 534–42.

50 Drusano GL, Liu W, Fikes S et al. Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumoniamodel. J Infect Dis 2014; doi:10.1093/infdis/jiu237.

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